Oxnard GR, et al. - Researchers evaluated the molecular mechanisms of acquired resistance to osimertinib and their clinical behavior. Findings suggested an association of acquired resistance to osimertinib mediated by loss of the T790M mutation with early resistance and a variety of competing resistance mechanisms. Clinical evidence about the heterogeneity of resistance in advanced non–small cell lung cancer (NSCLC) and a necessity for clinical trial approaches that can overcome multiple concomitant resistance mechanisms or strategies for preventing such resistance were provided in the findings.

Methods

• Experts identified patients with advanced NSCLC who got osimertinib for T790M-positive acquired resistance to prior EGFR tyrosine kinase inhibitor from a multi-institutional cohort (n=143) and a confirmatory trial cohort (n=110).
• They performed next-generation sequencing of tumor biopsies after osimertinib resistance.
• They studied the genotyping of plasma cell-free DNA as an orthogonal approach, including serial plasma samples when available.
• They finalized the study and analysis on November 9, 2017.
• The main outcomes included the mechanisms of resistance and their link with time to treatment discontinuation on osimertinib.

Results

• Out of the 143 patients evaluated, 41 (28 [68%] women) had tumor next-generation sequencing following acquired resistance to osimertinib.
• As per data, among 13 patients (32%) with maintained T790M at the time of resistance, 9 patients (22%) had EGFR C797S.
• Results demonstrated that among 28 individuals (68%) with loss of T790M, they detected a range of competing resistance mechanisms, including novel mechanisms such as acquired KRAS mutations and targetable gene fusions.
• In patients with T790M loss (6.1 vs 15.2 months), time to treatment discontinuation was shorter, thereby suggesting emergence of pre-existing resistant clones.
• In a validation cohort of 110 patients with plasma cell-free DNA genotyping performed after osimertinib resistance, this finding was confirmed.
• In studies of serial plasma levels of mutant EGFR, they noted an association of the loss of T790M at resistance with a smaller decrease in levels of the EGFR driver mutation after 1 to 3 weeks of therapy (100% vs 83% decrease; P=.01).